bims-malgli 2026-11-01 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2026–11–01
twelve papers selected by
Oltea Sampetrean, Keio University

Brain-sensing synNotch-CAR T cells enable precise targeting and clearance of diffuse midline glioma in multiple preclinical models.
Paracrine TMSB4X signaling from oligodendrocytes promotes diffuse glioma dissemination.
A long-term organotypic slice culture model of patient high-grade glioma preserving tumor heterogeneity and architecture, and specificity of CAR T cell targeting.
Blood-brain barrier-traversing multivalent TGFβ trap for anti-cancer immunomodulation of gliomas.
Macrophage lipid signaling drives glioblastoma invasion and represents a therapeutic vulnerability.
EGFR and TP53 mutations refine prognostic stratification of IDH-wildtype astrocytomas, not elsewhere classified.
EGFRvIII overexpression and loss of mouse-specific CDKN2A in glial cells leads to spontaneous gliomagenesis in a novel mouse model.
Glioma-derived ULBP2 triggers microglial extracellular traps formation via PAD4 lactylation to drive autophagy-dependent malignant growth.
Ex vivo glioblastoma migration phenotypes define clinical recurrence and tumor heterogeneity.
Lactate epigenetically shapes tumor cell states in H3K27M diffuse midline gliomas.
Spatial Neurophysiological Gradients at High Resolution Differentiate Tumor Types in the Human Cortex at the Tumor-Brain Interface.
FUCA1-Mediated Metabolic Adaptation Facilitates Lactylation-Induced Vasculogenic Mimicry in Glioblastoma.

Sci Transl Med. 2026 Oct 28. 18(873): eaed9994

Brain-sensing synNotch-CAR T cells enable precise targeting and clearance of diffuse midline glioma in multiple preclinical models.

Senthilnath Lakshmanachetty, Milos S Simic, Payal B Watchmaker, Robert Zhu, Takahide Nejo, Maggie Colton Cove, Jeffrey Haegelin, Haoyu Long, Aishi Zhao, Alejandra Bergquist, Wei Yu, Brianna Wong, Marco Gallus, Ricardo Almeida, Joanna P Phillips, Wendell A Lim, Hideho Okada.

Diffuse midline glioma (DMG) is a lethal pediatric brain tumor with limited therapeutic options and a poor prognosis. The success of chimeric antigen receptor (CAR) T cell therapy requires both improving T cell tumor infiltration and persistence and reducing the risk of on-target/off-tumor toxicity. Here, we adapted and advanced a brain-restricted CAR T cell platform previously validated in glioblastoma to address the anatomical and biological challenges of DMG. We engineered a T cell circuit in which a brain-specific synthetic Notch (synNotch) receptor recognizing brevican (BCAN) induced CAR expression against EphA2 or IL-13Rα2 ("B-SYNC"), thereby restricting CAR expression to the central nervous system (CNS). In immunodeficient DMG models, a single infusion of intravenous (iv) or intracerebroventricular (icv) B-SYNC circuit T cells led to tumor infiltration, sustained persistence, antitumor activity, and extended survival. An alternative BCAN-primed CAR targeting B7-H3 or IL-13Rα2 ("B-SYNC-B/I") similarly improved therapeutic efficacy when delivered intravenously. However, icv administration triggered fatal neurotoxicity because of low-level B7-H3 expression in nontumor CNS regions, indicating that rapid CNS exposure via icv delivery can amplify off-tumor toxicity. In contrast, in an immunocompetent syngeneic DMG model, both iv and icv delivery of a murinized BCAN-gated B7-H3 CAR (mB-SYNC-B7-H3) achieved durable tumor clearance and resistance to rechallenge without any detectable neurotoxicity. Mechanistically, synNotch-primed CAR T cells exhibited reduced exhaustion, enhanced activation, and enrichment of naïve and stem cell memory-like subsets. These findings demonstrate that brain-sensing synNotch CAR T circuits represent a generalizable and translatable strategy for targeting multiple CNS malignancies, including DMG.

DOI: https://doi.org/10.1126/scitranslmed.aed9994
Oncogene. 2026 Oct 26.

Paracrine TMSB4X signaling from oligodendrocytes promotes diffuse glioma dissemination.

Kit Man Chai, Cheng-Hsan Tsai, Min-Yi Lin, Ting-Chih Teng, Yi-Shiuan Chen, Shih-Jen Liu, Chuang-Rung Chang, Chih-Yen Wang.

White matter invasion underlies the lethality of diffuse glioblastoma (GBM), yet its microenvironmental drivers remain poorly defined. Here, we demonstrate that tumor-oligodendrocyte (OL) crosstalk actively promote white matter-associated glioma expansion. In the primary GBM or white matter-invasive glioma, OL lineage cells accumulate at tumor borders and enhance glioma proliferation and migration via secreted factors. Proteomic analysis combined with RNA sequencing identifies OL-derived TMSB4X (thymosin β-4) activates AKT signaling to sustain tumor expansion and invasion. Furthermore, glioma-derived TGF-β stimulates OL differentiation and TMSB4X production, establishing a feed-forward circuit that reinforces tumor progression. Critically, genetic or pharmacological blockade in tumor-OL interaction attenuates glioma outspreading along the white matter in vivo. These findings redefine the OLs as pro-invasive modulators and suggest OL-glioma crosstalk as a therapeutic target in diffuse GBM. Glioblastoma spreads through the brain's white matter while hijacking nearby oligodendrocytes. These cells release TMSB4X, which activates AKT signaling in tumor cells and promotes growth and invasion. In turn, tumors secrete TGF-β, which stimulates oligodendrocytes to produce more TMSB4X. This feed-forward loop may offer a new therapeutic target to prevent glioma from invading the white matter after surgical resection.

DOI: https://doi.org/10.1038/s41388-026-04029-8
bioRxiv. 2026 Oct 06. pii: 2026.10.04.756617. [Epub ahead of print]

A long-term organotypic slice culture model of patient high-grade glioma preserving tumor heterogeneity and architecture, and specificity of CAR T cell targeting.

Simiao Wang, Ching Ouyang, Heather N Zook, Massimo D'Apuzzo, Hsun Teresa Ku, Xiwei Wu, Angela S Baker, Yue Hao, Blake Brewster, Michael Berens, Behnam Badie, Christine E Brown, Michael E Barish.

   Background: High grade glioma (HGG), encompassing IDH-wildtype glioblastoma (CNS WHO grade 4), diffuse midline glioma (CNS WHO grade 4), oligodendroglioma (IDH-mutant and 1p/19q-codeleted) CNS WHO grade 3, together with IDH-mutant astrocytoma of CNS grade 3 and grade 4, represents the most lethal group of adult diffuse gliomas. Despite significant efforts, obtaining improvements in patient survival has been limited, in part, by difficulties in comprehensive ex vivo modeling of the complexities of HGG. Although organotypic slice cultures and other platforms have shown promise, existing models often fail to capture the intrinsic cellular heterogeneity, microenvironment, and architecture of HGG, restricting investigations into their fundamental biology as well as design of novel therapeutics.
Methods: We developed a patient-derived HGG organotypic slice culture (GOSC) platform demonstrating long-term preservation of intrinsic tumor characteristics. Vibratome-sectioned slices were cultured in defined medium under conditions approximating those in situ: reduced oxygen (4%), low glucose (2.5 mM), and no added growth factors. The characteristics of GOSCs after 28 days in culture, including expression of immunotherapy targets, were compared to parental tumors using histological staining, immunofluorescence, multiplexed PhenoCycler (CODEX) imaging, bulk RNA-seq expression profiling, and CAR T cell killing assays.
Results: GOSCs preserved the histopathology, cell heterogeneity, tumor microenvironment, and tissue architecture of their parental tumors throughout at least 28 days in culture. Importantly, GOSCs retained parental patterns of immunotherapy target expression, and CAR T cells co-cultured with GOSCs demonstrated target-specific killing consistent with parental tumors.
Conclusions: This ex vivo GOSC platform offers long-term preservation of the cellular and structural properties of parental HGG tumors, thereby providing a robust tool for extended preclinical studies, and facilitating development and evaluation of advanced tumor-targeting strategies.

Keywords:  CAR T cell immunotherapy; Organotypic slice culture; disease modeling; glioblastoma (GBM); high-grade glioma (HGG); tumor architecture; tumor heterogeneity

DOI:  https://doi.org/10.64898/2026.10.04.756617
bioRxiv. 2026 Oct 06. pii: 2026.10.05.756837. [Epub ahead of print]

Blood-brain barrier-traversing multivalent TGFβ trap for anti-cancer immunomodulation of gliomas.

Daiheon Lee, Seung Woo Chung, Byoungjae Kong, Yunxuan Xie, Bokyoung Kang, Jun Yang, Buwei Huang, Divya Rao, Jong Seob Choi, Eun A Ra, Pavlos Anastasiadis, Gabsang Lee, Deok-Ho Kim, Michael Lim, Jung Soo Suk.

Clinical studies have revealed that glioblastoma (GBM) is refractory to immunotherapy, such as immune checkpoint inhibitors (ICIs), due to the immunosuppressive tumor microenvironment (TME) primarily intensified by intratumoral upregulation of transforming growth factor-β (TGFβ). Primary GBM tumor bulks are surgically removed in clinic, but invasive tumor cells infiltrated into surrounding normal brain tissue cannot be eradicated by systemic therapy due to the integral blood-brain barrier (BBB), leading to near-inevitable tumor recurrence. To address these translational challenges, we have engineered a TGFβ-inhibiting protein nanocage comprising human heavy-chain ferritin protein and TGFβ receptor II ectodomain that enables BBB penetration and multivalent TGFβ entrapment, respectively. We demonstrate that the nanocage platform, denoted TβR2-HFt, following systemic administration, traverses the BBB, and extensively modulates immunosuppressive TME, both stromal and immune components, thereby potentiating the therapeutic efficacy of a clinically used ICI in multiple mouse glioma models. Notably, a majority of the glioma-bearing animals that received surgical tumor resection, followed by treatment with TβR2-HFt and the ICI, survived the tumor and resisted tumor rechallenge, providing a potential means to control GBM in a durable manner.
Teaser: BBB-traversing multivalent TGFβ trap reverses the immunosuppressive TME to rescue therapeutic efficacy of immune checkpoint blockade against GBM.

DOI: https://doi.org/10.64898/2026.10.05.756837
Cancer Cell. 2026 Oct 27. pii: S1535-6108(26)00472-1. [Epub ahead of print]

Macrophage lipid signaling drives glioblastoma invasion and represents a therapeutic vulnerability.

Carla Pallarés-Moratalla, Mélanie Guyot, Krish Skandha Gopalan, Bernhard Robl, Jakub Idkowiak, Jonas Dehairs, Nina Ravoet, Tim F E Hendriks, Kinga Anna Nowak, Nikolina Dubroja Lakić, Linqian Weng, Vasileios Konstantakos, Xander Spotbeen, Lutgarde Serneels, Sarah-Maria Fendt, Stein Aerts, Frederik De Smet, Eva Cuypers, Johannes V Swinnen, Gabriele Bergers.

  Glioblastoma (GBM) is characterized by diffuse infiltration into the surrounding brain, limiting complete surgical resection, the strongest determinant of patient survival. The mechanisms driving this invasive growth remain incompletely understood. Here, we identify a lipid-mediated paracrine signaling axis through which tumor-associated microglia/macrophages promote glioma invasion. Integrating single-cell transcriptomics, spatial lipidomics, and functional perturbation across mouse models and human GBM samples, we show that invading tumor cells engage and reprogram myeloid cells via colony-stimulating factor-1 receptor (CSF1R)-PI3K signaling. This induces lipid metabolic reprogramming and secretion of bioactive lipids, including lysophosphatidylcholines (LPCs) and lysophosphatidic acids (LPAs), which promote GBM invasion through distinct downstream pathways. Disruption of this myeloid-GBM axis reduces lipid secretion and suppresses invasion. Targeting downstream LPA-LPA receptor (LPAR) or YAP/TAZ signaling further constrains invasion in a context-dependent manner. Together, these findings define a lipid-driven circuit linking the tumor microenvironment to glioma invasion and identify strategies to reduce infiltration and improve surgical resection.

Keywords:  CSF1-CSF1R signaling; LPC/LPA; TAM; YAP/TAZ signaling; glioblastoma; invasion; lipid metabolism; spatial lipidomics; tumor-associated microglia/macrophage

DOI:  https://doi.org/10.1016/j.ccell.2026.10.006
Acta Neuropathol Commun. 2026 Aug 03. pii: 227. [Epub ahead of print]14(1):

EGFR and TP53 mutations refine prognostic stratification of IDH-wildtype astrocytomas, not elsewhere classified.

Nayuta Higa, Toshiaki Akahane, Seiya Yokoyama, Taiji Hamada, Hajime Yonezawa, Ryutaro Makino, Tomoko Takajo, Mari Kirishima, Ikumi Kitazono, Yutaka Fujioka, Ryusuke Hatae, Daisuke Kuga, Shohei Nagasaka, Kohei Suzuki, Junkoh Yamamoto, Koji Yoshimoto, Akihide Tanimoto, Ryosuke Hanaya.

  IDH-wildtype astrocytomas of histological grade 2 or 3 without the WHO 2021 molecular criteria for glioblastoma-TERT promoter mutation, EGFR amplification, or combined whole-chromosome 7 gain and 10 loss (+ 7/- 10)-are designated "Not Elsewhere Classified" (NEC), a residual category with clinical behavior ranging from indolent disease to courses clinically indistinguishable from glioblastoma (GBM). However, reliable molecular markers capable of resolving this heterogeneity have not been established. We retrospectively profiled a multi-institutional cohort comprising 38 adult IDH-wildtype astrocytoma NEC cases and 429 GBM controls using a bimodal DNA/RNA next-generation sequencing panel and, in 30 NEC cases, genome-wide DNA methylation profiling. NEC tumors were markedly heterogeneous: 21 of the 30 methylation profiles (70%) failed to match any reference class family, and the remaining nine were distributed across six categories, with Uniform Manifold Approximation and Projection (UMAP) showing scattered embedding adjacent to multiple high- and low-grade reference clusters, rather than a coherent NEC cluster. Against this heterogeneous background, two point mutations emerged as candidate markers for aggressive disease: EGFR mutations (3/38, 7.9%), all clustered in the extracellular domain, and TP53 mutations (8/38, 21.1%), predominantly in the DNA-binding domain. Both retained independent prognostic significance in Firth-penalized multivariate Cox regression (EGFR: HR 1.61, 95% CI 1.02-2.57, P = 0.028; TP53: HR 1.55, 95% CI 1.00-2.42, P = 0.041). NEC patients harboring EGFR and/or TP53 mutations showed an overall survival curve closely paralleling that of GBM (P = 0.9605) and significantly diverged from EGFR/TP53-wildtype NEC (P = 0.0011). Thus, despite the marked genomic and epigenomic heterogeneity within NEC, EGFR and TP53 point mutations may identify a high-risk NEC subgroup. This stratifier is deployable with routine targeted sequencing panels already widely used in diagnostic practice, and provides a practical refinement complementary to the cIMPACT-NOW Update 11 framework, pending prospective validation.

Keywords:   EGFR ; IDH-wildtype astrocytoma; TP53 ; DNA methylation profiling; Glioblastoma; Not elsewhere classified; Prognostic stratification

DOI:  https://doi.org/10.1186/s40478-026-02397-6
Neuro Oncol. 2026 Oct 24. pii: noag175. [Epub ahead of print]

EGFRvIII overexpression and loss of mouse-specific CDKN2A in glial cells leads to spontaneous gliomagenesis in a novel mouse model.

Olivia Singh, Yosef Ellenbogen, Mathew Voisin, Mira Li, Hafsah Ali, Qingxia Wei, Vikas Patil, Jeff Liu, Shirin Karimi, Mark Wilson, Sameer Agnihotri, Kenneth Aldape, Andrew Gao, Gelareh Zadeh.

   BACKGROUND: Glioblastoma is the most common primary brain cancer in adults, with a poor prognosis and median survival of 15 months after treatment. Few in vivo transgenic models exist for testing new therapeutics.
METHODS: A novel mouse model for the classical subtype of human glioblastoma (GBM) has been bred using Cre-mediated EGFRvIII overexpression and homozygous p19-ARF deletion, the mouse homolog of human p14ARF/CDKN2A, in GFAP-expressing cells.
RESULTS: Transgenic mice developed intraparenchymal and/or leptomeningeal brain lesions as early as 1 month old and 95% of mice succumb to endpoint symptoms of hydrocephalus and/or paralysis by 6 months. Immunohistochemical analysis confirms EGFRvIII overexpression and p19-ARF loss in Cre-expressing cells, along with patchy positive GFAP and high proliferation by Ki67 as well as loss of H3K27me3. Bulk and single cell RNA sequencing revealed tumors cluster closely with classical GBM and have significant upregulation of downstream markers in the JAK/STAT and P13K/AKT pathways as well as intratumoral heterogeneity. Dissociated tumors generated xenograft tumors by 3 weeks post intracranial injections into NOD-SCID mice and were characteristic of the primary lesion.
CONCLUSION: We developed a spontaneous, immune-competent murine glioma model that enables characterization of tumor development within an intact immune microenvironment and provides a resource for future mechanistic studies.

Keywords:  Glioblastoma; mouse model; neuro-oncology; tumor model

DOI:  https://doi.org/10.1093/neuonc/noag175
Oncogene. 2026 Oct 25.

Glioma-derived ULBP2 triggers microglial extracellular traps formation via PAD4 lactylation to drive autophagy-dependent malignant growth.

Ping Ma, Xiang Zhang, Jinghong Yang, Guanjian Zhao, Luping Xiao, Yuan Cheng, Jianhe Yue, Ning Huang.

The microglial extracellular traps(MiETs) were appeared in glioblastoma multiforme (GBM), but the underlying molecular mechanisms and functions were unknown. In this study, we aimed to explore the ability of GBM-derived UL16-binding protein 2 (ULBP2) on activating MiETs and manipulating microglia to support GBM development. Herein, ULBP2 was identified as a key upregulated protein in GBM and triggered MiETs formation. In turn, MiETs accelerated GBM malignant growth. Mechanistically, GBM released ULBP2 to connect with syndecan-1(SDC1) on microglia, the ULBP2/SDC1 complex induced lactylation of peptidylarginine deiminase 4 (PAD4) and following MiETs formation. Furthermore, MiETs stimulated GBM autophagy to promote proliferation and invasion. Our results demonstrated that GBM exerted a crucial role in MiETs formation through the ULBP2/SDC1/PAD4-Kla axis, and the interaction between GBM and microglia created a feed-forward mechanism for tumor progression. Thus, these data provided novel insights into a potential therapeutic target toward MiETs for preventing and suppressing GBM.

DOI: https://doi.org/10.1038/s41388-026-04031-0
bioRxiv. 2026 Sep 02. pii: 2026.08.31.748107. [Epub ahead of print]

Ex vivo glioblastoma migration phenotypes define clinical recurrence and tumor heterogeneity.

Jay Hou, Mariah McMahon, Andrew W Ni, Zhaoning Wang, Brett Taylor, Timothy Loe, Yang Xie, Lei Chang, Andrew Gardeck, Ziya Gokaslan, Shira I Dunsiger, Bing Ren, Clark C Chen, David J Odde.

Glioblastoma's pronounced migratory capacity underlies its diffuse invasion, presenting a formidable barrier to successful treatment. Ex vivo characterization of glioblastoma cells isolated from freshly resected clinical samples under physiologically relevant conditions revealed two distinct migratory phenotypes, Fast-Migrating (FM) and Slow-Migrating (SM). These phenotypes reflect distinct mechanosensitivity profiles and are associated with pharmacological responses that support the motor-clutch model of cell migration. Analysis of genes associated with these phenotypes revealed a transcriptomic signature that closely associated with in vitro cell migration, histological invasion in patient specimens, and clinical survival. Single-nucleus RNA sequencing revealed that FM and SM cells coexist within a single glioblastoma, with FM cells enriched at the periphery and SM cells localized to the tumor core. Collectively, our study demonstrates the utility of ex vivo glioblastoma characterization, allowing decoding of tumor heterogeneity and clinical prognostication as well as providing a framework for deconvoluting the complex cancer phenotype.

DOI: https://doi.org/10.64898/2026.08.31.748107
bioRxiv. 2026 Oct 06. pii: 2026.10.02.756321. [Epub ahead of print]

Lactate epigenetically shapes tumor cell states in H3K27M diffuse midline gliomas.

Joanna Lum, Nicholas Nuechterlein, Shelby Sliger, Sanjana Eyunni, Benita Tamrazi, Stefan Blüml, Wentao Tian, Akash Deogharkar, Stefan R Sweha, Mateus Mota, Jill Bayliss, Erik Peterson, Sunjong Ji, Molly Wittwer, Ksheetesha Bhat, Bryan T Mott, Erin T Hamanishi, Fjodor Merkuri, Ana Azambuja, Helena Conceicao, Fengyun Su, Xuhong Cao, Rishikesh Pandey, Omkar B Ljare, Abhijit Parolia, Viveka Nand Yadav, Daniel R Wahl, Carl Koschmann, Marcos Simoes-Costa, Kumar Pichumani, Shaomeng Wang, Arul M Chinnaiyan, Sriram Venneti.

H3K27M diffuse midline gliomas (DMGs) are lethal and lack treatment options. These tumors exhibit tumor heterogeneity with aggressive oligodendrocyte precursor (OPC)- and mesenchymal (MES)-like cell states. Because all tumor cells bear H3K27M, tumor heterogeneity has been attributed to microenvironmental cues that remain obscure. H3K27M DMGs exhibit increased glycolysis and the Warburg effect to produce lactate. Lactate can directly modify histone lysines including H3K27Lac, and we hypothesized that lactate epigenetically regulates tumor cell states in H3K27M DMGs. We undertook a comprehensive and integrated analysis of H3K27M DMG cell lines, animal models, tumor tissues, and magnetic resonance spectroscopy in patients to decipher the epigenetic roles of lactate. Here, we report that H3K27M cells uniquely exhibit elevation of the activating mark H3K27Lac. We observed significant heterogeneity in lactate levels within tumors, and the addition of exogenous lactate resulted in marked increases in H3K27Lac and the expression of critical OPC- and MES- like gene signature genes, which correlates with poorer patient outcomes. Our therapeutic approach leverages the inhibition of CBP/p300, which deposits both H3K27Lac and H3K27ac. Targeting CBP/p300 effectively reduces both H3K27Lac and H3K27ac levels, suppresses key OPC- and MES-like signatures, and shows efficacy in preclinical models. Collectively, our findings identify lactate as a key player in the epigenetic regulation of tumor cell state heterogeneity and suggest that targeting this pathway offers promise for addressing the heterogeneous complexities of H3K27M DMGs.

DOI: https://doi.org/10.64898/2026.10.02.756321
medRxiv. 2026 Oct 07. pii: 2026.10.05.26364665. [Epub ahead of print]

Spatial Neurophysiological Gradients at High Resolution Differentiate Tumor Types in the Human Cortex at the Tumor-Brain Interface.

Thomas Nelson, Brian Hsueh, Peter Hadar, Ipsita Das, Brian F Coughlin, Ayan S Mandal, Tommy Wilson, Emory Peng, Andrew Sho Perley, Haziq Rabbani, Roberto Ciordia, Jasmine Zou, Alan Bush, Matteo Vissani, Hazem Ghaith, James Cahill, Jimmy C Yang, William Muñoz, Erickson Torio, Adam C Glaser, Joshua D Bernstock, Kelly L Collins, Daniel R Cleary, Harmanpreet K Tiwana, Alexandra J Golby, Pamela S Jones, Bryan D Choi, Brian V Nahed, Ahmed M Raslan, Ziv M Williams, Shadi A Dayeh, Pranav Nanda, R Mark Richardson, Wenya Linda Bi, Steven Tobochnik, Daniel P Cahill, Gavin P Dunn, Sydney S Cash, Angelique C Paulk.

Brain tumors interact bidirectionally with neural circuits, but direct electrophysiological evidence in the human brain across tumor types remains limited. We analyzed intraoperative clinical, mesoscale, and high-density surface electroencephalography recordings from 100 participants undergoing tumor resection, epilepsy surgery, or deep brain stimulation. Population-averaged measures poorly separated diagnoses, whereas spatially resolved aperiodic exponent and high-gamma activity varied with both tumor distance and nearby tumor volume fraction across scales. Gradients differed among IDH-mutant glioma, IDH-wildtype glioblastoma, and metastases. Connectivity further distinguished infiltrative gliomas: beta coherence across tumor-brain connections was reduced in IDH-mutant tumors (p=0.0006; Kruskal-Wallis; mean coherence: tumor-brain 0.26, tumor-tumor 0.44, brain-brain 0.34), unlike IDH-wildtype tumors or metastases. Physiological abnormalities extended into radiographically normal-appearing brain, indicating tumor-type-dependent physiological signatures that may dynamically map the tumor-brain interface complementing structural imaging, with future possibilities as a spatial biomarker of tumor infiltration and network organization in humans.

DOI: https://doi.org/10.64898/2026.10.05.26364665
Cancer Res. 2026 Oct 29.

FUCA1-Mediated Metabolic Adaptation Facilitates Lactylation-Induced Vasculogenic Mimicry in Glioblastoma.

Jinxing Fu, Tianqi Liu, Qing Guo, Yuan Feng, Jinna Li, Ruikai Cai, Yang Liu, Longqiao Liu, Xiangyu Wang, Tao Sun, Jong Bae Park, Peng Cheng, Anhua Wu.

Vasculogenic mimicry (VM) is a process in which malignant cells acquire endothelial-like functions to generate perfusable vascular channels independent of endothelial cells. VM represents a major barrier to effective vascular endothelial growth factor A (VEGFA)-targeted therapy in cancer. In this study, we used organ-scale vascular imaging that identified a mechanism of VM in glioblastoma (GBM) mediated by alpha-L-fucosidase 1 (FUCA1). FUCA1 was preferentially expressed in glioblastoma stem-like cells (GSCs) with high CD44 expression. FUCA1 functioned as a key regulator of GSC-mediated VM by stabilizing LDHA protein and promoting a metabolic shift toward glycolysis. Elevated glycolytic flux increased lactate production and enhanced histone H3 lysine 18 lactylation (H3K18la), which in turn activated SERPINF1 transcription and drove VM in GSCs. In preclinical models, the FUCA1 inhibitor deoxyfuconojirimycin hydrochloride (DFH) significantly reduced GSC tumorigenicity and VM in vivo and exhibited robust antitumor activity when combined with anti-VEGFA therapy. Collectively, these findings define a FUCA1-mediated histone lactylation pathway that enhances GSC VM and highlight a therapeutically targetable mechanism to improve the efficacy of current anti-angiogenic strategies in GBM.

DOI: https://doi.org/10.1158/0008-5472.CAN-26-0035